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Article

pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis

1
Department of Parasitology and Tropical Medicine, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea
2
Department of Convergence Medical Science, Gyeongsang National University, Jinju 52727, Korea
*
Author to whom correspondence should be addressed.
Academic Editor: Petr Horák
Pathogens 2021, 10(9), 1128; https://doi.org/10.3390/pathogens10091128
Received: 12 May 2021 / Revised: 27 August 2021 / Accepted: 29 August 2021 / Published: 2 September 2021
(This article belongs to the Section Parasitic Pathogens)
Cathepsin D (CatD; EC 3.4.23.5) family peptidases of parasitic organisms are regarded as potential drug targets as they play critical roles in the physiology and pathobiology of parasites. Previously, we characterized the biochemical features of cathepsin D isozyme 2 (CatD2) in the carcinogenic liver fluke Clonorchis sinensis (CsCatD2). In this study, we performed all-atomic molecular dynamics simulations by applying different systems for the ligand-free/bound forms under neutral and acidic conditions to investigate the pH-dependent structural alterations and associated functional changes in CsCatD2. CsCatD2 showed several distinctive characteristics as follows: (1) acidic pH caused major conformational transitions from open to closed state in this enzyme; (2) during 30–36-ns simulations, acidic pH contributed significantly to the formation of rigid β-sheets around the catalytic residue Asp219, higher occupancy (0% to 99%) of hydrogen bond than that of Asp33, and enhanced stabilization of the CsCatD2-inhibtor complex; (3) neutral pH-induced displacement of the N-terminal part to hinder the accessibility of the active site and open allosteric site of this enzyme; and (4) the flap dynamics metrics, including distance (d1), TriCα angles (θ1 and θ2), and dihedral angle (ϕ), account for the asymmetrical twisting motion of the active site of this enzyme. These findings provide an in-depth understanding of the pH-dependent structural dynamics of free and bound forms of CsCatD2 and basic information for the rational design of an inhibitor as a drug targeting parasitic CatD. View Full-Text
Keywords: Clonorchis sinensis; cathepsin D; aspartic peptidase; molecular dynamics simulation; pH effect; flap dynamics Clonorchis sinensis; cathepsin D; aspartic peptidase; molecular dynamics simulation; pH effect; flap dynamics
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MDPI and ACS Style

Kang, J.-M.; Lê, H.G.; Na, B.-K.; Yoo, W.G. pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis. Pathogens 2021, 10, 1128. https://doi.org/10.3390/pathogens10091128

AMA Style

Kang J-M, Lê HG, Na B-K, Yoo WG. pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis. Pathogens. 2021; 10(9):1128. https://doi.org/10.3390/pathogens10091128

Chicago/Turabian Style

Kang, Jung-Mi, Hương Giang Lê, Byoung-Kuk Na, and Won Gi Yoo. 2021. "pH-Dependent Structural Dynamics of Cathepsin D-Family Aspartic Peptidase of Clonorchis sinensis" Pathogens 10, no. 9: 1128. https://doi.org/10.3390/pathogens10091128

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